Amphetamine During Adolescence Reroutes Mesolimbic Dopamine Axons to the Prefrontal Cortex via DCC Signaling

 描述(申请人提供)：青春期是个人最有可能开始滥用药物的时期。然而，在青春期开始吸毒也具有从娱乐用途发展为成瘾的最高风险。这表明，在青春期的关键时期接触药物可能会干扰正在进行的神经元发育，并导致行为变化，从而促进随后的药物滥用和成瘾。然而，对于药物暴露的这些年龄依赖效应的解释机制，仍然缺乏重大的了解。要解决我们知识中的这一差距，重要的是要了解(1)滥用药物与青少年大脑之间相互作用的潜在机制，(2)这些相互作用如何扰乱神经回路的发展，以及(3)由此导致的与成瘾相关的行为的长期变化。引导线索受体DCC最近成为青少年组织中皮质边缘多巴胺系统的关键分子，DCC的表达受到青少年滥用药物的调节。在青春期早期接触滥用的刺激性药物苯丙胺，通过改变DCC信号，扰乱小鼠内侧前额叶皮质多巴胺的输入。这项研究提出的长期目标是确定青春期苯丙胺是否通过扰乱DCC介导的指导事件将多巴胺轴突从边缘区域重新路由到前额叶皮质内侧，并确定对前额叶皮质依赖的认知行为的持久后果。这些神经生物学和行为变化可能是青春期开始吸毒的人更容易上瘾的原因。这些实验将在小鼠模型中使用神经解剖学、基因转基因和行为技术来评估三个特定的目标。目的1将确定青春期苯丙胺是否通过促进青春期中脑边缘多巴胺轴突的重路而增加前额叶皮质的多巴胺神经支配。目的2将评估DCC信号是否是青春期苯丙胺将中脑边缘多巴胺轴突重新路由到前额叶皮质的分子机制。目的3将确定DCC在调节青少年中皮质边缘多巴胺重组的长期行为后果中的作用。拟议中的研究结果将推动该领域更清楚地理解药物暴露对成瘾易感性的年龄相关性影响的机制。这些结果可用于促进针对青少年吸毒者的个性化预防和治疗战略的制定，因为青少年吸毒者发展成瘾的风险更高。

 DESCRIPTION (provided by applicant): Adolescence is the period in which individuals are most likely to initiate the consumption of drugs of abuse. The onset of drug use during adolescence, however, also confers the highest risk of progressing from recreational use to addiction. This suggests that drug exposure during the critical window of adolescence may interfere with ongoing neuronal development and cause behavioral changes which facilitate subsequent substance abuse and addiction. However, there is still a significant lack of knowledge about the mechanisms accounting for these age-dependent effects of drug exposure. To address this gap in our knowledge, it is important to understand (1) the mechanism underlying the interaction between drugs of abuse and the adolescent brain, (2) how these interactions disrupt the development of neuronal circuitry, and (3) the resulting long-lasting changes in addiction-relevant behaviors. The guidance cue receptor DCC has recently emerged as a key molecular player in the adolescent organization of the mesocorticolimbic dopamine system, and expression of DCC is regulated by adolescent exposure to drugs of abuse. Exposure to the stimulant drug of abuse, amphetamine, during early adolescence disrupts the development of dopamine input to the medial prefrontal cortex of mice via alterations to DCC signaling. The long-term goal of the studies proposed here is to determine if amphetamine in adolescence reroutes dopamine axons to the medial prefrontal cortex from limbic regions by disrupting DCC-mediated guidance events, and identify the enduring consequences on prefrontal cortex-dependent cognitive behavior. These neurobiological and behavioral alterations may underlie heightened vulnerability to progress to addiction in individuals that initiate drug use in adolescence. The experiments will employ neuroanatomical, gene transfection, and behavioral techniques in a mouse model to assess three specific aims. Aim 1 will determine whether amphetamine in adolescence increases prefrontal cortex dopamine innervation by promoting the rerouting of mesolimbic dopamine axons during adolescence. Aim 2 will assess whether DCC signaling is the molecular mechanism by which amphetamine in adolescence reroutes mesolimbic dopamine axons to the prefrontal cortex. Aim 3 will determine the role of DCC in mediating the long-term behavioral consequences of adolescent mesocorticolimbic dopamine reorganization. The results of the proposed research will move the field toward a clearer understanding of the mechanisms accounting for the age-dependent effects of drug exposure on addiction vulnerability. These results could be used to facilitate development of individualized prevention and treatment strategies aimed at adolescent drug users, who are at heightened risk to progress to addiction.